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Systematic mapping of genetic vulnerabilities in head and neck cancer

头颈癌遗传脆弱性的系统图谱

基本信息

批准号：
10054187
负责人：
Prashant Mali
金额：
$ 36.08万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-18 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10054187
关键词：
Bar Codes Biological Assay Biology CRISPR interference CRISPR screen CRISPR/Cas technology Cancer Biology Cancer cell line Cell Line Cells Cellular biology Cessation of life Chromosome Mapping Clustered Regularly Interspaced Short Palindromic Repeats Collection Coupled Data Data Set Dependovirus Development Disease Drug Combinations Drug Targeting Elements Epigenetic Process Exhibits Frequencies Gene Targeting Genes Genetic Genetic Epistasis Genetic Predisposition to Disease Genetic Screening Genome engineering Head and Neck Cancer Head and Neck Squamous Cell Carcinoma In Situ In Vitro Individual Knowledge Libraries Mali Malignant Neoplasms Maps Mediating Methodology Methods Modeling Molecular Target Mutagens Mutate Mutation Nature Oncogenic Pathway interactions Pharmaceutical Preparations Pharmacogenomics Pre-Clinical Model Prevention Primary Neoplasm Privatization Research Personnel Series Signal Pathway Technology Tissues Treatment Efficacy Tumor Biology Tumor Suppressor Proteins Validation Work anticancer research base cancer genome cancer therapy cancer type clinical predictors clinical translation clinically actionable clinically relevant combinatorial computer framework design driver mutation drug development experimental study genetic approach genome-wide head and neck cancer patient in vitro testing in vivo insight knockout gene novel patient derived xenograft model patient response personalized cancer therapy practical application precision oncology reverse genetics screening single cell analysis small molecule stem targeted cancer therapy tumor tumor heterogeneity tumor progression

项目摘要

Project Summary/Abstract A vast number of mutations contribute to cancer, but the observed non-random combinations of these leading to transformation highlight the importance of hallmark pathways and networks in cancer progression. While many pathways have been implicated in cancer, tumor heterogeneity stemming from different mutagens, tissue of origin, degree of progression, etc. leads to each case exhibiting a unique subset of altered pathways. Taken together, this diversity among cancer types and their origins, compounded by the huge genetic and epigenetic heterogeneity of tumors has complicated the development of targeted cancer treatments. The premise of this project is that cancer mutations converge into genetic interaction networks, and these networks bring together mutations of all varieties, including genes with low frequency of oncogenic mutations, and tumor suppressor profiles. We thus hypothesize that by systematically mapping these networks in both cell lines and in clinically relevant patient-derived xenograft (PDX) models, new molecular targets for cancer therapy can be identified. Focusing on head and neck squamous cell carcinomas (HNSCC), a disease that results in over 250,000 deaths each year worldwide, the aims correspondingly focus on using state-of-the-art high-throughput epistasis mapping via CRISPR-Cas and coupled single-cell analyses to enable systematic interrogation of the functions of individual genes and gene-pairs while notably also assaying the impact of tumor heterogeneity. Towards this we aim to utilize an extensive panel of >50 HNSCC cell lines and >50 PDX models. To enable screening across this vast collection we will utilize focused libraries and cell barcoding strategies that will allow us to efficiently screen across genes and cell panels via integrated pooled experiments. Coupled with rigorous in vitro and in vivo drug and targeted genetic validations in preclinical models, we anticipate our integrated experimental and computational framework will result in unprecedented insights into the underlying tumor biology as well as unraveling of clinically actionable genetic vulnerabilities to advance the practice of precision oncology.

项目总结/文摘